The differential role of the lipid raft-associated protein flotillin 2 for progression of myeloid leukemia - Archive ouverte HAL Access content directly
Journal Articles Blood Advances Year : 2022

The differential role of the lipid raft-associated protein flotillin 2 for progression of myeloid leukemia

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Eric Kowarz
Eliza Wiercinska
Rolf Marschalek

Abstract

Abstract Lipid raft-associated proteins play a vital role in membrane-mediated processes. The lipid microdomain-associated protein flotillin 2 (FLOT2), which has a scaffolding function, is involved in polarization, as well as in actin cytoskeletal organization of primitive and mature hematopoietic cells and has been associated with different malignancies. However, its involvement in myeloid leukemias is not well studied. Using murine transplantation models, we show here that the absence of FLOT2 from leukemia-initiating cells (LICs) altered the disease course of BCR-ABL1+ chronic myeloid leukemia (CML), but not of MLL–AF9-driven acute myeloid leukemia (AML). While FLOT2 was required for expression of the adhesion molecule CD44 on both CML- and AML-LIC, a defect in the cytoskeleton, cell polarity, and impaired homing ability of LIC was only observed in FLOT2-deficient BCR-ABL1+ compared with MLL-AF9+ cells. Downstream of CD44, BCR-ABL1 kinase-independent discrepancies were observed regarding expression, localization, and activity of cell division control protein 42 homolog (CDC42) between wild-type (WT) and FLOT2-deficient human CML and AML cells. Inhibition of CDC42 by ML141 impaired the homing of CML LIC and, thereby, CML progression. This suggested that alteration of both CD44 and CDC42 may be causative of impaired CML progression in the absence of FLOT2. In summary, our data suggest a FLOT2-CD44-CDC42 axis, which differentially regulates CML vs AML progression, with deficiency of FLOT2 impairing the development of CML.
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Dates and versions

hal-03758727 , version 1 (16-11-2022)

Identifiers

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Rahul Kumar, Raquel Pereira, Julian Niemann, Alexander Azimpour, Costanza Zanetti, et al.. The differential role of the lipid raft-associated protein flotillin 2 for progression of myeloid leukemia. Blood Advances, 2022, 6 (12), pp.3611-3624. ⟨10.1182/bloodadvances.2021005992⟩. ⟨hal-03758727⟩
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